Bila J. Pharmacological modulation of HSP70-mediated mechanisms of neuroprotection in cerebral ischemia

Molecular-biochemical mechanisms of the neuroprotective action of tamoxifen, melatonin, HSF-1 and glutamine, aimed at increasing the concentration of heat shock protein HSP70 in the ischemic brain, were investigated in the thesis. Increasing the HSP70 level results in an increase in the resistance of neurons to ischemic damage in in vitro and in vivo experiments. Tamoxifen, melatonin, HSF-1, and glutamine restored the energy metabolism of brain cells and reduced the manifestations of mitochondrial dysfunction. Thus, the mitochondrial membrane charge increased from 1.9 to 3.5 times (p<0.05), and the rate of opening of the mitochondrial pore decreased in the range from 1,5 to 2,5 times (p<0.05). The investigated drugs increased the level of ATP (by 50.4-101.8% (р<0.05)) against the background of a decrease in AMP (by 42.9-53.6% (р<0.05)). An increase in the level of malate (75-133.3% (p<0.05)) and pyruvate (47.8-108.7% (p<0.05)) was observed against the background of a decrease in lactate concentration (27.1-50.2%). Investigated drugs significantly (р<0.05) reduced mortality (HSF-1 by 50.8%, melatonin 46.4%, tamoxifen 41.2% and glutamine 32.5%) and manifestations of neurological deficiency (HSF-1 by 41.4%, melatonin 37.9%, tamoxifen 29.8% and glutamine 16.2%) on the 4th day of the experiment. Piracetam also reduced mortality (by 24.6% (p<0.05)) and neurological deficits (by 14%) of animals, but was inferior to the studied drugs. The most pronounced modulating activity against HSP70 was found by HSF-1. It was first established that the studied HSP70 modulators - tamoxifen, melatonin, HSF-1 and glutamine under conditions of acute experimental cerebral ischemia increase the expression of HSP70, HIF-1α and HIF-3α mRNA.